The study of neurocognitive impairment and its progression in HIV patients is a multifaceted endeavor involving complex data structures. These include multi-modal brain imaging measures as well as longitudinal host and viral markers. Exploring the full potential of these data requires the application and development of advanced statistical analysis methods. This proposal will address scientific questions motivated by the data obtained in Dr Ances' laboratory at Washington University in St. Louis. His extensive studies provide a unique opportunity to make inferences about the diagnosis and progression of neurocognitive impairment (NCI) among HIV-infected individuals. In this study, however, majority of the data is in the form of multi-modal brain images. Hence, the statistical analysis requires an innovative perspective that goes beyond mass univariate analyses or simple regression methods. Analysis of these data requires innovative methods which take a holistic view of these neuroimaging data with a mathematical and analytical framework that succeeds by incorporating adjunct co-informative data and clinical knowledge. This project answers these challenges with four aims focusing on determining imaging markers discriminating between HIV-infected patients and matched HIV-negative controls and establishing specific biomarkers of NCI diagnosis and progression among HIV-infected individuals. In Aim 1, we determine which structural and functional brain imaging markers discriminate between HIV- infected patients and matched HIV-negative controls. In Aim 2, we determine which structural and functional imaging markers predict neurocognitive impairment (NCI) severity in HIV-infected patients, whereas in Aim 3, we establish the imaging biomarkers predicting future NCI. Aim 4 is devoted to elucidating synergistic effects of aging and HIV infection on the NCI presence and progression. Thirty five million people worldwide are HIV-infected with over 40% having neurological or cognitive impairment. Despite the availability of combination antiretroviral therapy (cART), these individuals are at risk of accelerated brain degeneration, despite disease controlled in terms of undetectable virus. Our proposed methods directly address the study of brain degeneration and consequent cognitive impairment and thus have significant clinical and scientific impact. The developed methods are broadly applicable in a wide variety of complex data settings.